There is a critical unmet need for in vivo detection of dysplasia in patients with Barrett's esophagus (BE), a neoplastic tissue state resulting from chronic acid reflux. BE is associated with an increased risk of esophageal cancer, a disease with a high morbidity rate. Patients with BE undergo periodic endoscopic surveillance with systematic biopsy to search for pre-cancerous, dysplastic tissues, at which point therapeutic treatment by thermal ablation or surgery is indicated. These procedures are guided by white-light endoscopy but since there is no visual evidence of at the tissue surface, efficacy for detecting dysplasia is limited. Consequently, dysplasia goes undetected even though BE patients undergo regular endoscopic surveillance. Optical diagnostic techniques have shown the ability to assess tissue health in vivo but none has been widely adopted. Physicians have not taken up these techniques because they typically do not cover enough tissue area to be effective or lack sufficient sensitivity and specificity for real-time dysplasia detection. For example, angle-resolved low coherence interferometry (a/LCI) uses nuclear morphology measurements as a biomarker of dysplastic change, with proven sensitivity and specificity for in vivo detection of dysplastic BE tissues. However, a/LCI is a point probe modality, only examining tissues in one spot at a time. Here we seek to incorporate a/LCI into a multimodal optical imaging platform that enables practical detection of dysplasia in BE. The goal of this research project is to design, implement and test advanced multimodal optical imaging systems to enable diagnosis of dysplasia in BE tissues. The following specific aims are proposed. 1) Update a/LCI system with image guidance. The a/LCI system will be redesigned, capitalizing on advances in key spectrometer components to improve utility. The optical fiber probe will be updated to incorporate image guidance using optical coherence tomography (OCT), which will improve usability. 2) Implement real time feedback. Software will be updated to include real time guidance of tissue orientation and health status. 3) Test new designs in clinical study. Clinical study will confirm accuracy of a/LCI for detecting dysplasia while demonstrating improvements in efficiency of new hardware and software. A sub-aim of this study will be to evaluate OCT for guiding a/LCI measurements while also detecting residual sub-squamous BE glands which may persist after therapy that remain a cancer risk. 4) Develop multipoint a/LCI probe. Demonstrate principle of wide area scans using a/LCI, enabling multiple measurements without repositioning. Further advances will integrate this probe into the form factor of a therapeutic probe, specifically the Barrx Halo 90, a 2 cm2 ?paddle? that is mounted on the outside of a standard endoscope. 5) Conduct clinical trial of multipoint probe. This final clinical study will test the new form factor by comparing with the first trial in this project. Endpoints will be to determine the yield of dysplastic positive biopsies while also assessing the amount of time needed to cover the tissue. Completion of these aims will yield a clinically incisive diagnostic tool suitable for widespread adoption.